Why Does the Novel Coronavirus Spike Protein Interact so Strongly with the Human ACE2? A Thermodynamic Answer.
TL;DR: This work presents a chemical reason for the difficulty in treating the SARS‐CoV‐2 virus with drugs targeting its spike protein and helps to explain its infectiousness.
Abstract: The SARS-CoV-2 pandemic is the biggest health concern today, but until now there is no treatment. One possible drug target is the receptor binding domain (RBD) of the coronavirus' spike protein, which recognizes the human angiotensin-converting enzyme 2 (hACE2). Our in silico study discusses crucial structural and thermodynamic aspects of the interactions involving RBDs from the SARS-CoV and SARS-CoV-2 with the hACE2. Molecular docking and molecular dynamics simulations explain why the chemical affinity of the new SARS-CoV-2 for hACE2 is much higher than in the case of SARS-CoV, revealing an intricate pattern of hydrogen bonds and hydrophobic interactions and estimating a free energy of binding, which is consistently much more negative in the case of SARS-CoV-2. This work presents a chemical reason for the difficulty in treating the SARS-CoV-2 virus with drugs targeting its spike protein and helps to explain its infectiousness.
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TL;DR: It is shown that sugars attached to the N90 site of the human receptor interfere with binding to the virus, explaining reports of increased susceptibility to infection if N90 glycosylation is lost, and the N322 glycan binds to a conserved region of the spike protein identified previously as a cryptic epitope for a neutralizing antibody.
Abstract: Binding of the spike protein of SARS-CoV-2 to the human angiotensin-converting enzyme 2 (ACE2) receptor triggers translocation of the virus into cells. Both the ACE2 receptor and the spike protein are heavily glycosylated, including at sites near their binding interface. We built fully glycosylated models of the ACE2 receptor bound to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Using atomistic molecular dynamics (MD) simulations, we found that the glycosylation of the human ACE2 receptor contributes substantially to the binding of the virus. Interestingly, the glycans at two glycosylation sites, N90 and N322, have opposite effects on spike protein binding. The glycan at the N90 site partly covers the binding interface of the spike RBD. Therefore, this glycan can interfere with the binding of the spike protein and protect against docking of the virus to the cell. By contrast, the glycan at the N322 site interacts tightly with the RBD of the ACE2-bound spike protein and strengthens the complex. Remarkably, the N322 glycan binds to a conserved region of the spike protein identified previously as a cryptic epitope for a neutralizing antibody. By mapping the glycan binding sites, our MD simulations aid in the targeted development of neutralizing antibodies and SARS-CoV-2 fusion inhibitors.
97 citations
TL;DR: In this paper, the authors considered drug repurposing as an attractive approach that can facilitate the drug discovery process by reusing existing pharmaceuticals to treat illnesses other than their primary indications.
Abstract: The rapid and global spread of a new human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Here, we consider drug repurposing as an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. We review current information concerning the global health issue of COVID-19 including promising approved drugs, e.g., human angiotensin-converting enzyme inhibitors (hACEIs). Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in-silico studies of drug development efforts against SARS-CoV-2. Alacepril and lisinopril were found to interact with human angiotensin-converting enzyme 2 (hACE2), the host entranceway for SARS-CoV-2 spike protein, through exhibiting the most acceptable rmsd_refine values and the best binding affinity through forming a strong hydrogen bond with Asn90, which is assumed to be essential for the activity, as well as significant extra interactions with other receptor-binding residues. Furthermore, molecular dynamics (MD) simulations followed by calculation of the binding free energy were also carried out for the most promising two ligand-pocket complexes from docking studies (alacepril and lisinopril) to clarify some information on their thermodynamic and dynamic properties and confirm the docking results as well. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19. Eventually, animal experiments and accurate clinical trials are needed to confirm the potential preventive and treatment effect of these compounds.
94 citations
TL;DR: In this paper , the authors performed a detailed investigation to provide an understanding of the impact of these novel mutations on the structure, function, and binding of RBD to hACE2 and mAb to the NTD of the spike protein.
49 citations
Abbas Khan1, J. J. Gui, W. Ahmad2, I. Haq3, M. Shahid4, Azhar Abbas Khan5, Abdullah Shah6, L. Ali7, Zeeshan Anwar2, Muhammad Safdar8, J. Abubaker, N. N. Uddin9, L. Q. Cao10, Dong-Qing Wei1, A. Mohammad •
TL;DR: Insight is provided into the binding and structural-dynamics changes resulting from novel mutations in the RBD and NTD and the need for further in vitro and in vivo studies is suggested to facilitate the development of possible therapies for new variants of SARS-CoV-2.
Abstract: Continuing reports of new SARS-CoV-2 variants have caused worldwide concern and created a challenging situation for clinicians. The recently reported variant B.1.618, which possesses the E484K mutation specific to the receptor-binding domain (RBD), as well as two deletions of Tyr145 and His146 at the N-terminal binding domain (NTD) of the spike protein, must be studied in depth to devise new therapeutic options. Structural variants reported in the RBD and NTD may play essential roles in the increased pathogenicity of this SARS-CoV-2 new variant. We explored the binding differences and structural-dynamic features of the B.1.618 variant using structural and biomolecular simulation approaches. Our results revealed that the E484K mutation in the RBD slightly altered the binding affinity through affecting the hydrogen bonding network. We also observed that the flexibility of three important loops in the RBD required for binding was increased, which may improve the conformational optimization and consequently binding of the new variant. Furthermore, we found that deletions of Tyr145 and His146 at the NTD reduced the binding affinity of the monoclonal antibody (mAb) 4A8, and that the hydrogen bonding network was significantly affected consequently. This data show that the new B.1.618 variant is an antibody-escaping variant with slightly altered ACE2–RBD affinity. Moreover, we provide insights into the binding and structural-dynamics changes resulting from novel mutations in the RBD and NTD. Our results suggest the need for further in vitro and in vivo studies that will facilitate the development of possible therapies for new variants such as B.1.618.
49 citations
TL;DR: In this paper, structural and biomolecular simulation techniques were used to explore the impact of specific mutations (L452R-E484Q) in the B.1.617 variant on the binding of RBD to the host receptor ACE2.
Abstract: The evolution of new SARS-CoV-2 variants around the globe has made the COVID-19 pandemic more worrisome, further pressuring the health care system and immunity. Novel variations that are unique to the receptor-binding motif (RBM) of the receptor-binding domain (RBD) spike glycoprotein, i. e. L452R-E484Q, may play a different role in the B.1.617 (also known as G/452R.V3) variant's pathogenicity and better survival compared to the wild type. Therefore, a thorough analysis is needed to understand the impact of these mutations on binding with host receptor (RBD) and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to explore the impact of specific mutations (L452R-E484Q) in the B.1.617 variant on the binding of RBD to the host receptor ACE2. Our analysis revealed that the B.1.617 variant possesses different dynamic behaviours by altering dynamic-stability, residual flexibility and structural compactness. Moreover, the new variant had altered the bonding network and structural-dynamics properties significantly. MM/GBSA technique was used, which further established the binding differences between the wild type and B.1.617 variant. In conclusion, this study provides a strong impetus to develop novel drugs against the new SARS-CoV-2 variants.
38 citations
References
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TL;DR: In this article, the authors compared the Bernal Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P potential functions for liquid water in the NPT ensemble at 25°C and 1 atm.
Abstract: Classical Monte Carlo simulations have been carried out for liquid water in the NPT ensemble at 25 °C and 1 atm using six of the simpler intermolecular potential functions for the water dimer: Bernal–Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P. Comparisons are made with experimental thermodynamic and structural data including the recent neutron diffraction results of Thiessen and Narten. The computed densities and potential energies are in reasonable accord with experiment except for the original BF model, which yields an 18% overestimate of the density and poor structural results. The TIPS2 and TIP4P potentials yield oxygen–oxygen partial structure functions in good agreement with the neutron diffraction results. The accord with the experimental OH and HH partial structure functions is poorer; however, the computed results for these functions are similar for all the potential functions. Consequently, the discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons are also made for self‐diffusion coefficients obtained from molecular dynamics simulations. Overall, the SPC, ST2, TIPS2, and TIP4P models give reasonable structural and thermodynamic descriptions of liquid water and they should be useful in simulations of aqueous solutions. The simplicity of the SPC, TIPS2, and TIP4P functions is also attractive from a computational standpoint.
33,683 citations
TL;DR: AutoDock4 incorporates limited flexibility in the receptor and its utility in analysis of covalently bound ligands is reported, using both a grid‐based docking method and a modification of the flexible sidechain technique.
Abstract: We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.
15,616 citations
TL;DR: In this paper, a new Lagrangian formulation is introduced to make molecular dynamics (MD) calculations on systems under the most general externally applied, conditions of stress, which is well suited to the study of structural transformations in solids under external stress and at finite temperature.
Abstract: A new Lagrangian formulation is introduced. It can be used to make molecular dynamics (MD) calculations on systems under the most general, externally applied, conditions of stress. In this formulation the MD cell shape and size can change according to dynamical equations given by this Lagrangian. This new MD technique is well suited to the study of structural transformations in solids under external stress and at finite temperature. As an example of the use of this technique we show how a single crystal of Ni behaves under uniform uniaxial compressive and tensile loads. This work confirms some of the results of static (i.e., zero temperature) calculations reported in the literature. We also show that some results regarding the stress‐strain relation obtained by static calculations are invalid at finite temperature. We find that, under compressive loading, our model of Ni shows a bifurcation in its stress‐strain relation; this bifurcation provides a link in configuration space between cubic and hexagonal close packing. It is suggested that such a transformation could perhaps be observed experimentally under extreme conditions of shock.
13,937 citations
TL;DR: GROMACS is one of the most widely used open-source and free software codes in chemistry, used primarily for dynamical simulations of biomolecules, and provides a rich set of calculation types.
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TL;DR: In this paper, the authors present a new molecular dynamics algorithm for sampling the canonical distribution, where the velocities of all the particles are rescaled by a properly chosen random factor.
Abstract: The authors present a new molecular dynamics algorithm for sampling the canonical distribution. In this approach the velocities of all the particles are rescaled by a properly chosen random factor. The algorithm is formally justified and it is shown that, in spite of its stochastic nature, a quantity can still be defined that remains constant during the evolution. In numerical applications this quantity can be used to measure the accuracy of the sampling. The authors illustrate the properties of this new method on Lennard-Jones and TIP4P water models in the solid and liquid phases. Its performance is excellent and largely independent of the thermostat parameter also with regard to the dynamic properties.
11,327 citations